The overall goals of the Yale SPORE in Skin Cancer (YSPORE) are to improve prevention, diagnosis and treatment of melanomas by performing translational studies in four subjects: a) (Genomic sunlight dosimeters for melanoma prevention (Project 1); b) The B7-H1/PD-1 pathway in melanoma immunity (Project 2); c) Molecular diversity of melanomas and response to targeted (Project 3); and d) The RACil pathway as a target for melanoma therapy (Project 4). The program includes Developmental Research and Career Development Programs, Biospecimen Resource and Bioinformatics/Biostatistics Cores that support the translational research needs of all investigators in the YSPORE. The YSPORE is led by an Administration Core that coordinates and manages the program on a daily basis. One of the overriding themes of the YSPORE is to reveal biomarkers and targets for therapy based on Information from Next-Generation (Next-Gen) DNA sequencing, genomics and proteomics analyses. This approach will be used to identify: 1) regions of the genome that are sensitive indicators of long-term accumulation of DNA damage and mutations resulting from sunlight exposure; and 2) the molecular basis of resistance of melanomas to targeted therapy with BRAF inhibitors (BRAFi). We will use structure function analyses to identify druggable targets in resistant cells (Project 3) and in a novel RAC1 pathway that we have identified in melanoma (Project 4). Project 2 is dedicated to one of the most promising immunotherapy for melanoma, anti PD-1, and is focused on tumor/stroma interactions to reveal mechanism of evasion of cancer immunity. The studies in this project should have direct impact for current development of B7-H1/PD-1 blockade as a novel and promising approach for melanoma therapy. The expected translational outcomes of the program are: 1) Development of biological indicators for sun exposure risk to be used in melanoma prevention; 2) The identification of predictive biomarkers for therapeutic blockade of the PD-1/PD-L1 pathway and the role of this pathway in resistance to other types of immunotherapy, leading to potentially more effective combination immunotherapy; 3) The development of molecular tests that will guide treatment for BRAFi; 4) The classification of melanoma according to therapeutic options based on mutations in 'driver' pathway; 5) identification of small molecule that can target the RAC1 pathway; 6) The implementation of new national initiatives such as the CaTISSUE, The Cancer Genome Atlas (TCGA) and the MRF National Consortium for melanoma clinical trials.